Novel bicyclic scents

ABSTRACT

Novel 2-methylene-3-methyl-3-(1&#39;,3&#39;-pentadien-1&#39;-yl)-bicyclo-[2,2,1]-heptanes substituted in the 4&#39;-position by methyl, alkoxycarbonyl, formyl, hydroxymethyl or cyano are obtained by reacting the novel aldehyde 2-methylene-3-methyl-3-formyl-bicyclo-[2,2,1]-heptane with 3-methyl-, 3-alkoxycarbonyl- or acetalized 3-formyl-2-butene-1-triarylphosphorylidene under the conditions of a Wittig reaction, with or without hydrolytic cleavage of the acetal group, or hydrolytic cleavage of the acetal group followed by reduction of the formyl group to the hydroxymethyl group, or hydrolytic cleavage of the acetal group, reaction of the aldehyde with a hydroxylammonium salt, and dehydration of the resulting oxime. 
     The novel compounds are distinguished by interesting scent characteristics.

The present invention relates to novel compounds of the general formulaI ##STR1## where R¹ is --CH₂ OH, --CHO, --COOCH₃, --COOC₂ H₅, --CN or--CH₃ and to processes for their preparation.

The novel compounds possess interesting scent characteristics and henceconstitute an enrichment of the range of valuable fully synthetic scentsand hence also an enrichment of the art.

The compound of the formula I, where R is --CH₂ OH, has a particularlyinteresting fragrance. The carbon skeleton of the novel compoundsresembles the skeleton of a sought-after natural fragrance materialobtained from sandalwoods, viz. β-santalol ##STR2## The compound of theformula I, where R is --CH₂ OH, could be described asdehydro-β-santalol.

The novel compounds of the general formula I, where R¹ is --CH₃,--COOCH₃ or --COOC₂ H₅ may advantageously be prepared by a methodwherein the aldehyde of the formula II ##STR3## is reacted, under theconditions of a Wittig reaction, with a phosphorylide of the generalformula III ##STR4## where the Ar radicals are identical or differentaryl, especially phenyl or tolyl, or cyclohexyl, and R¹ has the abovemeaning.

The novel compound of the general formula I, where R¹ is --CHO, may beobtained by a method wherein the aldehyde of the formula II ##STR5## isreacted, under conditions of a Wittig reaction, with a phosphorylide ofthe general formula III ##STR6## where R² is the acetal group ##STR7##R³ and R⁴ being an aliphatic hydrocarbon radical of 1 to 4 carbon atomsor R³ and R⁴ together being an ethylene or propylene radical which maybe substituted by one or more alkyl of 1 to 4 carbon atoms, preferablymethyl, and the Ar radicals are identical or different aryl, especiallyphenyl or tolyl or cyclohexyl, and the resulting acetal is hydrolyzedunder acid conditions in the conventional manner.

The compounds of the formula I, where R¹ is --CH₂ OH, may be obtained bya method wherein

(A) the aldehyde of the formula II ##STR8## is reacted, under theconditions of a Wittig reaction, with a phosphorylide of the generalformula III ##STR9## where R² is an acetal group ##STR10## R³ and R⁴being an aliphatic hydrocarbon radical of 1 to 4 carbon atoms or R³ andR⁴ together being an ethylene or propylene radical which may besubstituted by one or more alkyl of 1 to 4 carbon atoms, preferablymethyl, and the Ar radicals are identical or different aryl, especiallyphenyl or tolyl or cyclohexyl.

(B) the resulting acetal is hydrolyzed under acid conditions in theconventional manner and

(C) the resulting aldehyde of the general formula I is reduced withLiAlH₄ or by the Meerwein-Ponndorf method with aluminum isopropylate.

The compound of the formula I, where R¹ is --CN, may be obtained by amethod wherein

(A) the aldehyde II ##STR11## is reacted, under the conditions of aWittig reaction, with a phosphorylide of the general formula III##STR12## where R² is an acetal group ##STR13## R³ and R⁴ being analiphatic hydrocarbon radical of 1 to 4 carbon atoms or R³ and R⁴together being an ethylene or propylene radical which may be substitutedby one or more alkyl of 1 to 4 carbon atoms, especially methyl, and theAr radicals are identical or different aryl, especially phenyl or tolylor cyclohexyl,

(B) the resulting acetal is hydrolyzed under acid conditions in theconventional manner,

(C) the resulting aldehyde of the general formula I is converted to theoxime by means of a hydroxylammonium salt, in the conventional manner,and

(D) the resulting oxime is dehydrated in the conventional manner.

The essential reaction step in the preparation of the novel bicyclicscents, which is common to all cases, is the Wittig reaction between thealdehyde of the formula II and a phosphorylide of the general formulaIII.

The aldehyde II, (2-methylene-3-methyl-3-formylbicyclo-[2,2,1]-heptane)has hitherto neither been synthesized nor characterized. A publicationin Helv. Chim. Acta 59 (1976), 738 states that certain experimentalindications suggest that the bicyclic teresantalal II also occurs insandalwood oil. The aldehyde II can be obtained from the novel compound2-chloromethyl-3-methyl-3-formylbicyclo-[2,2,1]-heptane (described inGerman Patent Application No. P 27 19 976, which however does notconstitute a prior publication) by elimination of HCl, whilst protectingthe formyl group by acetalizing. The compound boils at 74°-78° C./0.2 mmHg.

The phosphorylides may be prepared in the conventional manner, forexample by treating the phosphonium salts, on which they are based, withstrong bases. Further details are to be found, inter alia, in thesummary by Tripett (Quart. Reviews, 17 (1963), 406 et seq.).

An advantageous method of carrying out the reaction according to theinvention is to prepare the phosphorylide from the correspondingphosphonium salt directly in the solvent envisaged for the Wittigsynthesis, and if appropriate even in the presence of the aldehyde to beconverted. The requisite phosphonium salts can be prepared by a simpleconventional method, namely reaction of the corresponding alkyl halides,especially the corresponding alkyl chlorides, with triarylphosphines ortricyclohexylphosphine, especially with triphenylphosphine.

The bases conventionally used for Wittig syntheses may be used as thestrong bases for the preparation of the phosphorylides. Examples includealkali metal hydroxides, alkali metal hydrides, alkali metal amides,alkali metal alcoholates, alkaline earth metal alcoholates,phenyllithium and butyl-lithium, sodium alcoholates and potassiumalcoholates being preferred.

Ethylene oxide (see Angew. Chem. 80 (1968), 535 et seq.) and excessphosphorylide can, under certain conditions, also take the place of thestrong base.

Suitable solvents for the preparation of the phosphorylides, and for theWittig reaction, are the solvents conventionally used for Wittigsyntheses, for example aliphatic or aromatic hydrocarbons, eg. hexane,octane, cyclohexane, benzene, toluene and xylene and their halogenationproducts, alcohols, eg. methanol, ethanol, isopropanol, butanols,hexanols, cyclohexanol and cyclooctanol as well as glycols, ethers, eg.diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran,dimethyltetrahydrofuran and dioxane, or mixtures of these. Polar organicsolvents, eg. methanol, ethanol, formamide, dimethylformamide,N-methylpyrrolidone, hexamethylphosphorotriamide, acetonitrile anddimethylsulfoxide, and mixtures of these solvents, are particularlysuitable. The process of the invention can also be carried out in wateror in aqueous mixtures.

The reaction according to the invention of the aldehyde II with thephosphorylidene III is advantageously carried out by introducing aphosphonium salt of the formula IV ##STR14## where X is chlorine,bromine or iodine and R¹ or R² and Ar have the above meanings, and abouta stoichiometric amount of the aldehyde to be reacted, into a solventand then adding about a stoichiometric amount of a strong base inportions to this suspension at from -20° to +70° C., preferably from 0°to 30° C., whilst stirring, with or without cooling, and introducing drynitrogen. The reaction mixture is then kept at from 15° to 30° C.,preferably at room temperature, for from 1 to 24 hours, preferably from1 to 2 hours.

However, the reaction according to the invention can also be carried outby adding about the stoichiometric amount of a strong base to thesolution of the phosphonium salt at the above temperature, then addingthe aldehyde of the formula II to the phosphorylide solution obtainedabove, and thereafter allowing the reaction to finish as describedabove.

In total, from about 1 to 1.2 moles of base are used per mole ofphosphonium salt for the above reaction. The reaction mixture is workedup in the conventional manner by separating the reaction product fromthe triarylphosphine oxide or tricyclohexylphosphine oxide formed, forexample by extraction and distillation, with or without subsequentpreparative chromatography.

The acid hydrolysis of the acetal obtained by the Wittig reaction of thealdehyde II with the phosphorylidene III containing an acetal group iscarried out in the conventional manner. For example, the acetal isadvantageously treated with from 0.01 to 1 mole, per mole of acetal, ofa mineral acid, eg. sulfuric acid or hydrochloric acid, or an organicacid, eg. formic acid or p-toluenesulfonic acid or acetic acid, in theform of a solution of from 1 to 20 percent strength, and the batch isheated, with thorough mixing, for from 0.5 to 5 hours, preferably from 2to 3 hours, at from 10° to 50° C.

For the hydrolysis, it is advisable to add a solubilizing agent to thereaction mixture. Particularly suitable solubilizing agents are loweraliphatic alcohols, eg. methanol, ethanol and propanol, as well ascycloaliphatic ethers, eg. tetrahydrofuran and dioxane. The aldehydeobtained can be isolated in the conventional manner, for example byextraction after gently neutralizing the reaction mixture, for examplewith an alkali metal bicarbonate or sodium carbonate, and distilling offthe extractant.

The aldehyde of the formula I can be reduced in the conventional manner,by means of LiAlH₄, NaBH₄ or aluminum isopropylate, to give the alcoholof the formula I.

The solvent used for the reaction with LiAlH₄ is preferably an ether,eg. diethyl ether or tetrahydrofuran (THF). Advantageously, it is usedin an amount of from about 1/4 to 1 mole per mole of aldehyde. Thereaction temperature is in general from room temperature to the refluxtemperature of the solvent. The reaction time is from about 1 to 6hours.

LiAlH₄ is introduced into an anhydrous solvent (in which it is partiallydissolved and partially suspended). The carbonyl compound, in therelevant solvent, is slowly added to this mixture. Depending on thereactivity of the carbonyl compound, the reaction may have finishedafter stirring for several hours at room temperature, or may requireheating for several hours.

Excess LiAlH₄ is destroyed by carefully adding an alcohol, eg. ethanol.The organic phase is washed with water, dried and concentrated. Thereaction product is purified in the conventional manner, for example bydistillation.

The reaction with NaBH₄ is in general carried out in protic solvents,eg. water or ethanol, the latter being preferred. Advantageously, it isused in an amount of from about 1/4 to 1 mole per mole of carbonylcompound. The reaction is in general carried out at room temperature;the reaction time is from about 2 to 12 hours.

The reaction mixture is worked up in the conventional manner, forexample by decomposing the residue with a dilute acid and thenextracting with a solvent.

For the reduction of the aldehyde of the formula I with aluminumisopropylate (Meerwein-Ponndorf-Verley reduction), the solvent used isanhydrous isopropyl alcohol. To carry out the reduction, the Alisopropylate is introduced into isopropanol and the carbonyl compound isadded to this mixture. From 1/3 to 2 moles of Al isopropylate are usedper mole of carbonyl compound. On heating the mixture, acetone isformed, and this is distilled off through a column. The reaction is ingeneral carried out at from about 60° to 120° C. and the reaction timeis from about 30 to 60 minutes.

When no further acetone is formed, the residue is decomposed with diluteacid and the product is isolated, for example by extraction with asolvent.

To convert the aldehyde of the formula I to the oxime, it isadvantageous to add to the carbonyl compound an equivalent amount, or aslight excess, of a hydroxylammonium salt, eg. hydroxylammonium chlorideor hydroxylammonium sulfate, in water or alcohol or in a mixture ofthese.

The reaction is in general carried out at from room temperature to theboiling point of the solvent. Bases, eg. hydroxides, carbonates,bicarbonates, acetates or the like are added in order to neutralize theacid liberated and give a pH, in the reaction mixture, of from about 4to 5.

To work up the mixture, water is added and the oxime is isolated byextraction with a solvent.

A dehydration of the oxime is also carried out in the conventionalmanner by reaction with a dehydrating agent, eg. an anhydride or acidchloride or P₂ O₅, or by thermal elimination of water. Advantageously,the oxime is heated for several hours with a large excess of aceticanhydride. The reaction is in general carried out at from roomtemperature to the boiling point of the particular solvent. The reactiontime is from about 1 to several hours. The solvent used is either theoxime itself or an aprotic solvent, for example a chlorohydrocarbon, eg.CH₂ Cl₂ or CHCl₃ ; a hydrocarbon, eg. toluene or xylene, or an ether,eg. dioxane or tetrahydrofuran. The mixture is generally worked up bydecomposition with water and extraction with a solvent.

The novel bicyclic compounds possess interesting scent characteristicsand hence broaden the range of available valuable fully syntheticfragrance materials.

EXAMPLE 1

73 g (0.2 mole) of 3-methyl-2-butene-1-triphenylphosphonium chloride aresuspended in 200 ml of THF. 0.22 mole of butyl-lithium, in the form of138 ml of a 1.6 N solution of butyl-lithium in hexane, is addeddropwise, whilst cooling. The contents of the flask turn deep red. 29 g(0.2 mole) of the aldehyde2-methylene-3-methyl-3-formyl-bicyclo-[2,2,1]-heptane in 50 ml of THFare then added dropwise and the reaction mixture is heated for 6 hoursat 50° C.

The solution is then concentrated, the residue is extracted by boilingwith petroleum ether and the solution in the latter solvent is washedwith aqueous methanol, dried and concentrated. This leaves a residue of38.6 g.

Subsequent distillation gives 3 g of the aldehyde starting material and30.6 g of2-methylene-3-methyl-3-(4'-methyl-1',3'-pentadien-1'-yl)-bicyclo-[2,2,1]-heptane(II) boiling at 65° C./0.01 mm Hg; n_(D) ²⁵ =1.5260. The IR and NMRspectra confirm the structure; the NMR spectrum indicates a mixture ofthe exo and endo compounds. The yield is 82%, based on aldehydeconverted. Scent: pleasantly woody.

EXAMPLE 2

85 g (0.2 mole) of 3-ethoxycarbonyl-2-butene-1-triphenylphosphoniumchloride are reacted, by the method described in Example 1, with 138 mlof a 1.6 N butyllithium solution (corresponding to 1.1 times the molaramount) in hexane and then with 29 g (0.2 mole) of2-methylene-3-methyl-3-formyl-bicyclo-[2,2,1]-heptane. In addition to14.3 g of unconverted aldehyde, 6.2 g of2-methylene-3-methyl-3-(4'-ethoxycarbonyl-1',3'-pentadien-1'-yl)-bicyclo-[2,2,1]-heptaneboiling at 150° C./0.01 mm Hg are obtained; n_(D) ²⁵ =1.5312. The yieldis 24%, based on aldehyde converted.

Scent: sweet, fruity, aniseed-like.

EXAMPLE 3

(a) 90.5 g (0.2 mole) of3-(4'-methyl-1',3'-dioxan-2'-yl)-2-butene-1-triphenylphosphoniumchloride are reacted, by the method described in Example 1, with 138 mlof a 1.6 N butyl-lithium solution in hexane and then with 29 g of thealdehyde II. In addition to 19 g of unconverted aldehyde, 18.6 g of2-methylene-3-methyl-3-[4'-(4"-methyl-1",3"-dioxan-2"-yl)1',3'-pentadien-1'-yl]-bicyclo-[2,2,1]-heptane,boiling at 160° C./0.01 mm Hg, are obtained; n_(D) ²⁵ =1.5233. The IRand NMR spectra confirm the structure. The yield is 93%, based onaldehyde converted.

(b) 27 g of the acetal obtained as described in 3 (a) are stirred with50 ml of 10 percent strength aqueous H₂ SO₄ and 50 ml of dioxane for 2hours at 20° C. The reaction mixture is then diluted with 50 ml of waterand extracted with ether. The ether extracts are washed neutral withbicarbonate solution, dried and concentrated.

10 g of2-methylene-3-methyl-3-(4'-formyl-1',3'-pentadien-1'-yl)-cicyclo-[2,2,1]-heptane,boiling at 103°-106° C./0.2 mm Hg, are obtained; the IR and NMR spectraconfirm the structure. The yield is 50%, based on aldehyde II employed.

Scent: fresh, woody.

EXAMPLE 4

9.2 g (0.0426 mole) of the aldehyde obtained as described in 3 (b) aredissolved in 20 ml of ethanol and the solution is added dropwise to amixture of 0.6 g (0.015 mole) of NaBH₄ and 50 ml of ethanol. Thereaction mixture is stirred for 4 hours at 20° C. and is thenconcentrated, water is added and the mixture is rendered slightly acidwith dilute H₂ SO₄ and is extracted with ether. The resulting organicphase is dried and concentrated. On subsequent distillation, 6.4 g of2-methylene-3-methyl-3-(4'-hydroxymethyl-1',3'-pentadien-1'-yl)-bicyclo-[2,2,1]-heptaneboiling at 130° C./0.08 mm Hg are obtained. In a refrigerator, theproduct solidifies to a wax. The IR and NMR spectra confirm thestructure. The yield is 70%, based on acetal employed.

Scent: balsamy, woody, mild.

EXAMPLE 5

6 g of hydroxylammonium chloride, 6 g of Na acetate and 40 g of waterare added to 9 g of the bicyclic aldehyde obtained as described inExample 3 (b) and the resulting mixture is heated for 30 minutes at 60°C. It is then cooled, 50 ml of water are added, the mixture is extractedwith ether and the combined ether phases are concentrated. 20 g ofacetic anhydride are added to the resulting crude oxime and the mixtureobtained is refluxed for 2 hours. Water is then added, the mixture isextracted with ether and the ether phase obtained is neutralized, driedand concentrated. The residue is purified by chromatography on silicagel, using a 3:1 petroleum ether/ether mixture as the eluent. 5.4 g of2-methylene-3-methyl-3-(4'-cyano-1',3'-pentadien-1'-yl)-bicyclo-[2,2,1]-heptane,boiling at 100°-105° C./0.2 mm Hg, are obtained. The yield is 61%, basedon aldehyde employed. The scent resembles that of the aldehyde of theformula I, but is somewhat fruitier.

We claim:
 1. A compound of the formula I ##STR15## where R¹ is --CH₂ OHor --CHO.
 2. A compound as set forth in claim 1 wherein R¹ is --CH₂ OH.3. A compound as set forth in claim 1 wherein R¹ is --CHO.